Introduction: Females exhibit protection from renal ischemia-reperfusion injury (IRI) compared to males in animal models and in human kidneys transplants. Previous experiments have shown that estrogen receptor alpha (ERa) plays an important role in mediating this protection in female mice. We wished to investigate further the mechanisms underlying ERa-mediated protection.

Methods: Wild-type (B6) and ERa knockout (ERaKO) C57BL/6 mice underwent 15-min warm IRI with clamping of the left renal pedicle and contralateral nephrectomy. Syngeneic renal isografts were transplanted between female WT and ERaKO mice with minimal cold ischemic time, followed by native nephrectomy and 25-min warm IRI of the transplanted kidney. BUN and creatinine were measured daily for 4 days following injury and kidneys were collected for histology after 28 days.

Results: Male ERaKO mice demonstrated equivalent biochemical renal injury (p=0.81, Fig1A) and fibrosis compared to B6 controls. In transplant experiments, mice with extra-renal ERaKO (B6->ESRaKO) demonstrated increased IRI vulnerability compared to renal-restricted ERaKO (ERaKO->B6) or control (B6->B6) mice (p<0.05, Figs 1B & C).

Conclusions: Genetic deletion of ERa increases vulnerability to renal IRI in female but not male mice. This increased vulnerability persists when ERaKO is confined to extra-renal tissue in females, but not when ERaKO is confined to the kidney. This finding confirms that sex-specific differences in renal IRI are partially mediated by estrogens and their receptors and suggests that ERa plays a role in female protection through mechanisms extrinsic to the kidney.

CITATION INFORMATION: Aufhauser D., Murken D., Concors S., Wang Z., Ge G., Bhatti T., Hancock W., Levine M. Extra-Renal Effects of Estrogen Receptor-Alpha Mediate Protection from Renal Ischemia-Reperfusion Injury Am J Transplant. 2017;17 (suppl 3).

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